Pyrrolo[2,3-d]pyrimidine compounds

ABSTRACT

A compound of the formula  
                 
 
     wherein R 1 , R 2  and R 3  are as defined above, which are inhibitors of the enzyme protein tyrosine kinases such as Janus Kinase 3 and as such are useful therapy as immunosuppressive agents for organ transplants, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn&#39;s disease, Alzheimer&#39;s disease, Leukemia and other autoimmune diseases.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to pyrrolo[2,3-d]pyrimidinecompounds which are inhibitors of protein tyrosine kinases, such as theenzyme Janus Kinase 3 (hereinafter also referred to as JAK3) and as suchare useful therapy as immunosuppressive agents for organ transplants,lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type Idiabetes and complications from diabetes, cancer, asthma, atopicdermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn'sdisease, Alzheimer's disease, Leukemia and other indications whereimmunosuppression would be desirable.

[0002] This invention also relates to a method of using such compoundsin the treatment of the above indications in mammals, especially humans,and the phamaceutical compositions useful therefor.

[0003] JAK3 is a member of the Janus family of protein tyrosine kinases.Although the other members of this family are expressed by essentiallyall tissues, JAK3 expression is limited to hematopoetic cells. This isconsistent with its essential role in signaling through the receptorsfor IL-2, IL-4, IL-7, IL-9 and IL-15 by non-covalent association of JAK3with the gamma chain common to these multichain receptors. XSCID patientpopulations have been identified with severely reduced levels of JAK3protein or with genetic defects to the common gamma chain, suggestingthat immunosuppression should result from blocking signaling through theJAK3 pathway. Animal studies have suggested that JAK3 not only plays acritical role in B and T lymphocyte maturation, but that JAK3 isconstitutively required to maintain T cell function. Modulation ofimmune activity through this novel mechanism can prove useful in thetreatment of T cell proliferative disorders such as transplant rejectionand autoimmune diseases.

SUMMARY OF THE INVENTION

[0004] The present invention relates to a compound of the formula

[0005] or the pharmaceutically acceptable salt thereof; wherein

[0006] R¹ is a group of the formula

[0007] wherein the dashed line represents optional double bonds;

[0008] m is 0, 1, 2 or 3;

[0009] n is 0, 1, 2 or 3;

[0010] X, B and D are each independently oxygen, S(O)_(d) wherein d is0, 1 or 2, NR⁶ or CR⁷R⁸;

[0011] A and E are each CR⁷R⁸; and

[0012] R⁶ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)alkyl(difluoromethylene), (C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl,(C₁-C₆)alkoxy(C₁-C₆)acyl, (C₁-C₆)alkylamino(C₁-C₆)acyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, (C₆-C₁₀)aryl, (C₅-C₉)heteroaryl,(C₆-C₁₀)aryl(C₁-C₆)alkyl, (C₅-C₉)heteroaryl(C₁-C₆)alkyl,(C₆-C₁₀)aryl(C₆-C₁₀)aryl, (C₆-C₁₀)aryl(C₆-C₁₀)aryl(C₁-C₆)alky,(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, hydroxy(C₂-C₆)alkyl,(C₁-C₆)acyloxy(C₂-C₆)alkyl, (C₁-C₆)alkoxy(C₂-C₆)alkyl,piperazinyl(C₁-C₆)alkyl, (C₁-C₆)acylamino(C₁-C₆)alkyl,(C₆-C₁₀)aryl(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₅-C₉)heteroaryl(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkylthio(C₁-C₆)alkyl, (C₆-C₁₀)arylthio(C₁-C₆)alkyl,(C₁-C₆)alkyosulfinyl(C₁-C₆)alkyl, (C₆-C₁₀)arylsulfinyl(C₁-C₆)alkyl,(C₁-C₆)alkylsulfonyl(C₁-C₆)alkyl, (C₆-C₁₀)arylsulfonyl(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl, R¹³CO(C₁-C₆)alkyl wherein R¹³ is R²⁰Oor R²⁰R²¹N wherein R²⁰ and R²¹ are each independently selected from thegroup consisting of hydrogen, (C₁-C₆)alkyl, (C₆-C₁₀)aryl(C₁-C₆)alkyl or(C₅-C₉)heteroaryl(C₁-C₆)alkyl; or R¹⁴(C₂-C₆)alkyl wherein R¹⁴ is(C₁-C₆)acylpiperazino, (C₆-C₁₀)arylpiperazino,(C₅-C₉)heteroarylpiperazino, (C₁-C₆)alkylpiperazino,(C₆-C₁₀)aryl(C₁-C₆)alkylpiperazino,(C₅-C₉)heteroaryl(C₁-C₆)alkylpiperazino, morpholino, thiomorpholino,piperidino, pyrrolidino, piperidyl, (C₁-C₆)alkylpiperidyl,(C₆-C₁₀)arylpiperidyl, (C₅-C₉)heteroarylpiperidyl,(C₆-C₁₀)aryl(C₁-C₆)alkylpiperidyl,(C₅-C₉)heteroaryl(C₁-C₆)alkylpiperidyl, (C₁-C₆)alkoxyacyl,(C₁-C₆)alkylaminoaryl, ((C₁-C₆)alkyl₂aminoacyl or (C₁-C₆)acylpiperidyl;

[0013] R⁷ and R⁸ are each independently selected from the groupconsisting of hydrogen, deuterium, (C₁-C₆)alkyl, amino, hydroxy,(C₁-C₆)alkoxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)amino, (C₁-C₆)acylamino,(C₁-C₆)acyl(C₁-C₆)alkylamino, carboxy, (C₁-C₆)alkoxyacyl,(C₁-C₆)alkylaminoacyl, ((C₁-C₆)alkyl)₂aminoacyl, aminoacyl,trifluoromethyl, trfluoromethyl(C₁-C₆)alkyl, (C₁-C₆)alkyl(difluoromethylene), (C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl,(C₆-C₁₀)aryl, (C₅-C₉)heteroaryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl,(C₅-C₉)heteroaryl(C₁-C₆)alkyl, (C₆-C₁₀)aryl(C₆-C₁₀)aryl,(C₆-C₁₀)aryl(C₆-C₁₀)aryl(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,piperazinyl(C₁-C₆)alkyl, (C₁-C₆)acylamino(C₁-C₆)alkyl, piperidyl,(C₁-C₆)alkylpiperidyl, (C₆-C₁₀)aryl(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₅-C₉)heteroaryl(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkylthio(C₁-C₆)alkyl, (C₆-C₁₀)arylthio(C₁-C₆)alkyl,(C₁-C₆)alkylsulfinyl(C₁-C₆)alkyl, (C₆-C₁₀)arylsulfinyl(C₁-C₆)alkyl,(C₁-C₆)alkylsulfonyl(C₁-C₆)alkyl, (C₆-C₁₀)arylsulfonyl(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl, R¹³CO(C₁-C₆)alkyl orR¹³CO(C₃-C₁₀)cycloalkyl wherein R¹³ is R²⁰O or R²⁰R²¹N wherein R²⁰ andR²¹ are each independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₆-C₁₀)aryl(C₁-C₆)alkyl or(C₅-C₉)heteroaryl(C₁-C₆)alkyl; R¹⁴, R¹⁴(C₁-C₆)alkyl orR¹⁴(C₃-C₁₀)cycloalkyl wherein R¹⁴ is (C₁-C₆)acylpiperazino,(C₆-C₁₀)arylpiperazino, (C₅-C₉)heteroarylpiperazino,(C₁-C₆)alkylpiperazino, (C₆-C₁₀)aryl(C₁-C₆)alkylpiperazino(C₅-C₉)heteroaryl(C₁-C₆)alkylpiperazino, morpholino, thiomorpholino,piperidino, pyrrolidino, piperidyl, (C₁-C₆)alkylpiperidyl,(C₆-C₁₀)arylpiperidyl, (C₅-C₉)heteroarylpiperidyl,(C₆-C₁₀)aryl(C₁-C₆)alkylpiperidyl,(C₅-C₉)heteroaryl(C₁-C₆)alkylpiperidyl or (C₁-C₆)acylpiperidyl; or agroup of the formula

[0014] wherein p is 0, 1, 2 or 3; and

[0015] Z is hydroxy, (C₁-C₆)alkoxy or NR¹R² wherein R¹ and R² are eachindependently selected from the group consisting of hydrogen,(C₁-C₆)alkyl, piperidyl, (C₁-C₆)alkylpiperidyl, (C₆-C₁₀)arylpiperidyl,(C₅-C₉)heteroarylpiperidyl, (C₆-C₁₀)aryl(C₁-C₆)alkylpiperidyl,(C₅-C₉)heteroaryl(C₁-C₆)alkylpiperidyl, (C₁-C₆)acylpiperidyl,(C₆-C₁₀)aryl, (C₅-C₉)heteroaryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl,(C₅-C₉)heteroaryl(C₁-C₆)alkyl, (C₆-C₁₀)aryl(C₆-C₁₀)aryl,(C₆-C₁₀)aryl(C₆-C₁₀)aryl(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, R⁵(C₁-C₆)alkyl,(C₁-C₅)alkyl(CHR⁵)(C₁-C₆)alkyl wherein R⁵ is hydroxy, (C₁-C₆)acyloxy,(C₁-C₆)alkoxy, piperazino, (C₁-C₆)acylamino, (C₁-C₆)alkylthio,(C₆-C₁₀)arylthio, (C₁-C₆)alkylsulfinyl, (C₆-C₁₀)arylsulfinyl,(C₁-C₆)alkylsulfoxyl, (C₆-C₁₀)arylsulfoxyl, amino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂ amino, (C₁-C₆)acylpiperazino, (C₁-C₆)alkylpiperazino,(C₆-C₁₀)aryl(C₁-C₆)alkylpiperazino,(C₅-C₉)heteroaryl(C₁-C₆)alkylpiperazino, morpholino, thiomorpholino,piperidino or pyrrolidino; R⁶(C₁-C₆)alkyl,(C₁-C₅)alkyl(CHR⁶)(C₁-C₆)alkyl wherein R⁶ is piperidyl,(C₁-C₆)alkylpiperidyl, (C₆-C₁₀)arylpiperidyl,(C₆-C₁₀)aryl(C₁-C₆)alkylpiperidyl, (C₅-C₉)heteroarylpiperidyl or(C₅-C₉)heteroaryl(C₁-C₆)alkylpiperidyl;

[0016] or when n is at least 1, D and E, or D and X, are each CR⁷R⁸, theadjacent R⁷ groups may be taken together, with the carbons to which theyare attached, to form groups of the formulas

[0017] wherein the dashed lines represent optional double bonds;

[0018] a is 0, 1 or 2;

[0019] m, A, B and X are as defined above; and

[0020] G, J, L and M are each independently oxygen, S(O)_(d) wherein dis 0, 1 or 2, NR⁶ or CR⁷R⁸ wherein R⁶, R⁷ and R⁸ are as defined above;

[0021] or when n is 1, D and E are each CR⁷R⁸ and m is 1, A and B areeach CR⁷R⁸, the respective adjacent R⁷ groups may be taken together,with the carbons to which they are attached, to form a group of theformula

[0022] wherein the dashed bond represent optional double bonds;

[0023] a, G, J. L and M are as define above;

[0024] r is 0 or 1;

[0025] c is 0, 1 or 2; and

[0026] R, W, Y and S are each independently oxygen, S(O)_(d) wherein dis 0, 1 or ₂, NR⁶ or CR⁷R⁸ wherein R⁶, R⁷ and R⁸ are as defined above;

[0027] R² and R³ are each independently selected from the groupconsisting of hydrogen, deuterium, amino, halo, hydoxy, nitro, carboxy,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, trifluoromethyl, trifluoromethoxy,(C₁-C₆)alkyl, (C₁-C₆)alkoxy wherein the alkyl or alkoxy groups areoptionally substittued by one to three groups selected from halo,hydroxy, carboxy, amino (C₁-C₆)alkylthio, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, (C₅-C₉)heteroaryl, (C₂-C₉)heterocycloalkyl,(C₃-C₉)cycloalkyl or (C₆-C₁₀)aryl; or R² and R³ are each independently(C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkoxy, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, (C₆-C₁₀)arylamino, (C₁-C₆)alkylthio,(C₆-C₁₀)arylthio, (C₁-C₆)alkylsulfinyl, (C₆-C₁₀)arylsulfinyl,(C₁-C₆)alkylsulfonyl, (C₆-C₁₀)arylsulfonyl, (C₁-C₆)acyl,(C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyamino-CO—, (C₅-C₉)heteroaryl,(C₂-C₉)heterocycloalkyl or (C₆-C₁₀)aryl wherein the heteroaryl,heterocycloalkyl and aryl groups are optionally substituted by one tothree halo, (C₁-C₆)alkyo, (C₁-C₆)alkyl-CO—NH—, (C₁-C₆)alkoxy-CO—NH—,(C₁-C₆)alkyl-CO—NH—(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH—(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH—(C₁-C₆)alkoxy, carboxy, carboxy(C₁-C₆)alkyl,carboxy(C₁-C₆)alkoxy, benzyloxycarbonyl(C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₆-C₁₀)aryl, amino,amino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonylamino,(C₆-C₁₀)aryl(C₁-C₆)alkoxycarbonylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, (C₁-C₆)alkylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, carboxy,carboxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH—,(C₁-C₆)alkyl-CO—NH—, cyano, (C₅-C₉)heterocycloalkyl, amino-CO—NH—,(C₁-C₆)alkylamino-CO—NH—, ((C₁-C₆)alkyl)₂amino-CO—NH—,(C₆-C₁₀)arylamino-CO—NH—, (C₅-C₉)heteroarylamino-CO—NH—,(C₁-C₆)alkylamino-CO—NH—(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino-CO—NH—(C₁-C₆)alkyl,(C₆-C₁₀)arylamino-CO—NH—(C₁-C₆)alkyl,(C₅-C₉)heteroarylamino-CO—NH—(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl,(C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₆-C₁₀)arylsulfonyl, (C₆-C₁₀)arylsulfonylamino,(C₆-C₁₀)arylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₅-C₉)heteroaryl or(C₂-C₉)heterocycloalkyl;

[0028] with the proviso that when A, B or X, in formulas V or VI, isdefined as NR⁶ or CR⁷R⁸, R² and/or R³ must be halo;

[0029] with the proviso that when R² and R³ are each independentlyhydrogen or (C₁-C₆)alkyl, R¹ cannot be unsubstituted piperidinyl;

[0030] with the proviso that when R² and R³ are each hydrogen, R¹ cannotbe unsubstituted mopholinyl or pyrrolidinyl;

[0031] with the proviso that when R² and R³ are each hydrogen, R¹ cannotbe piperazinyl; and

[0032] with the proviso that the groups of formuls IV, V, VI or XIII donot contain two or more oxygens, sulfurs or combinations thereof inadjacent positions.

[0033] The present invention also relates to the pharmaceuticallyacceptable acid addition salts of compounds of the formula I. The acidswhich are used to prepare the pharmaceutically acceptable acid additionsalts of the aforementioned base compounds of this invention are thosewhich form non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, acetate, lactate, citrate, acid citrate, tartrate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

[0034] The invention also relates to base addition salts of formula I.The chemical bases that may be used as reagents to preparepharmaceutically acceptable base salts of those compounds of formula Ithat are acidic in nature are those that form non-toxic base salts withsuch compounds. Such non-toxic base salts include, but are not limitedto those derived from such pharmacologically acceptable cations such asalkali metal cations (e.g., potassium and sodium) and alkaline earthmetal cations (e.g., calcium and magnesium), ammonium or water-solubleamine addition salts such as N-methylglucamine-(meglumine), and thelower alkanolammonium and other base salts of pharmaceuticallyacceptable organic amines.

[0035] The term “alkyl”, as used herein, unless otherwise indicated,includes saturated monovalent hydrocarbon radicals having straight,branched or cyclic moieties or combinations thereof.

[0036] The term “alkoxy”, as used herein, includes O-alkyl groupswherein “alkyl” is defined above.

[0037] The term “halo”, as used herein, unless otherwise indicated,includes fluoro, chloro, bromo or iodo.

[0038] The compounds of this invention may contain double bonds. Whensuch bonds are present, the compounds of the invention exist as cis andtrans configurations and as mixtures thereof.

[0039] Unless otherwise indicated, the alkyl and alkenyl groups referredto herein, as well as the alkyl moieties of other groups referred toherein (e.g., alkoxy), may be linear or branched, and they may also becyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl) or be linear or branched and contain cyclic moieties.Unless otherwise indicated, halogen includes fluorine, chlorine,bromine, and iodine.

[0040] (C₃-C₁₀)Cycloalkyl when used herein refers to cycloalkyl groupscontaining zero to two levels of unsaturation such as cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,1,3-cyclohexadiene, cycloheptyl, cycloheptenyl, bicyclo[3.2.1]octane,norbornanyl etc..

[0041] (C₂-C₉)Heterocycloalkyl when used herein refers to pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl,thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl,isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,tetrahydroazepinyl, piperazinyl, chromanyl, etc. One of ordinary skillin the art will understand that the connection of said(C₂-C₉)heterocycloalkyl rings is through a carbon or a sp³ hybridizednitrogen heteroatom.

[0042] (C₂-C₉)Heteroaryl when used herein refers to furyl, thienyl,thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl,triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyt, pyridazino,1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl,pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl,6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl,5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyo, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl, benzoxazinyl; etc. One of ordinary skill inthe art will understand that the connection of said(C₂-C₉)heterocycloalkyl rings is through a carbon atom or a sp³hybridized nitrogen heteroatom.

[0043] (C₆-C₁₀)aryl when used herein refers to phenyl or naphthyl.

[0044] Compounds of formula (I) may be administered in apharmaceutically acceptable form either alone or in combination with oneor more additional agents which modulate a mammalian immune system orwith antiinflammatory agents. These agents may include but are notlimited to cyclosporin A (e.g. Sandimmune® or Neoral®, rapamycin, FK-506(tacrolimus), leflunomide, deoxyspergualin, mycophenolate (e.g.Cellcept®), azathioprine (e.g. Imuran®)), daclizumab (e.g. Zenapax®.OKT3 (e.g. Orthoclone®), AtGam, aspirin, acetaminophen, ibuprofen,naproxen, piroxicam, and antiinflammatory steroids (e.g. prednisolone ordexamethasone). These agents may be administered as part of the same orseparate dosage forms, via the same or different routes ofadministration, and on the same or different administration schedulesaccording to standard pharmaceutical practice.

[0045] The compounds of this invention include all configurationalisomers (e.g., cis and trans isomers) and all optical isomers ofcompounds of the formula I (e.g., enantiomers and diastereomers), aswell as racemic, diastereomeric and other mixtures of such isomers. Thisinvention also includes all rotamers of compounds of formula I as wellas scelemic mixtures.

[0046] Preferred compounds of formula I include those wherein R¹ is is agroup of the formula

[0047] wherein the dashed line represents optional double bonds;

[0048] m is 0, 1, 2 or 3;

[0049] n is 0, 1, 2 or 3;

[0050] X, B and D are each independently oxygen, S(O)_(d) wherein d is0, 1 or 2, NR⁶ or CR⁷R⁸;

[0051] A and E are each independently CR⁷R⁸or NR⁶;

[0052] or when n is 1, D and E are each CR⁷R⁸ and m is 1, A and B areeach CR⁷R⁸, the respective adjacent R⁷ groups may be taken together,with the carbons to which they are attached, to form a group of theformula

[0053] wherein the dashed bond represent optional double bonds;

[0054] a, G, J. L and M are as define above;

[0055] r is 0 or 1;

[0056] c is 0, 1 or 2; and

[0057] R, W, Y and S are each independently oxygen, S(O)_(d) wherein dis 0, 1 or 2, NR⁶ or CR⁷R⁸ wherein R⁶, R⁷ and R⁸ are as defined above.

[0058] Other preferred compounds of formula I include those wherein R²and R³ are each independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl,(C₃-C₁₀)cycloalkoxy, (C₂-C₉)heterocycloalkyl, (C₅-C₉)heteroaryl or(C₆-C₁₀)aryl.

[0059] Specific preferred compounds of formula I include the following:

[0060] 5-Fluoro-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine;

[0061] 4-Piperidin-1-yl-5-trifluoromethyl-7H-pyrrolo[2,3-d]pyrimidine;

[0062]2-{3-Ethyl-4-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-cyclopentyl}-propan-2-ol;

[0063]2-{3-Ethyl-4-[(2-hydroxy-ethyl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-cyclopentyl}-propan-2-ol;

[0064]N,N-Dimethyl-N′-[3-(4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-benzyl]-ethane-1,2-diamine;

[0065]2-[1-(5-m-Tolyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-ethanol;

[0066]5-(3-Isopropyl-phenyl)-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine;

[0067]5-(3-Methyl-3H-imidazol-4-yl)-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine;

[0068]5-(1-Methyl-1H-imidazol-4-yl)-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine;

[0069]5-(2-Methyl-pyridin-4-yl)-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine;

[0070] 5-Chloro-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine;

[0071] 5-Chloro-4-(octahydro-indol-1-yl)-7H-pyrrolo[2,3-d]pyrimidine;

[0072] 5-Ethynyl-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine;

[0073] 4-Piperidin-1-yl-5-m-tolyl-7H-pyrrolo[2,3-d]pyrimidine; and

[0074] 4-(3,3-Dimethyl-piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine.

[0075] The present invention also relates to a pharmaceuticalcomposition for (a) treating or preventing a disorder or conditionselected from organ transplant rejection, lupus, multiple sclerosis,rheumatoid arthritis, psoriasis, Type I diabetes and complications fromdiabetes, cancer, asthma, atopic dermatitis, autoimmune thyroiddisorders, ulcerative colitis, Crohn's disease, Alzheimer's disease,Leukemia, and other autoimmune diseases or (b) the inhibition of proteintyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including ahuman, comprising an amount of a compound of formula I or apharmaceutically acceptable salt thereof, effective in such disorders orconditions and a pharmaceutically acceptable carrier.

[0076] The present invention also relates to a pharmaceuticalcomposition for (a) treating or preventing a disorder or conditionselected from organ transplant rejection, lupus, multiple sclerosis,rheumatoid arthritis, psoriasis, Type I diabetes and complications fromdiabetes, cancer, asthma, atopic dermatitis, autoimmune thyroiddisorders, ulcerative colitis, Crohn's disease, Alzheimer's disease,Leukemia, and other autoimmune diseases or (b) the inhibition of proteintyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including ahuman, comprising an amount of a compound of formula I or apharmaceutically acceptable salt thereof, alone or in combination withT-cell immunosuppressant or antiinflammatory agents, effective in suchdisorders or conditions and a pharmaceutically acceptable carrier.

[0077] The present invention also relates to a method for the inhibitionof protein typrosine kinases or Janus Kinase 3 (JAK3) in a mammal,including a human, comprising administering to said mammal an effectiveamount of a compound of formula I or a pharmaceutically acceptable saltthereof.

[0078] The present invention also relates to a method for treating orpreventing a disorder or condition selected from organ transplantrejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis,Type I diabetes and complications from diabetes, cancer, asthma, atopicdermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn'sdisease, Alzheimer's disease, Leukemia, and other autoimmune diseases ina mammal, including a human, comprising administering to said mammal anamount of a compound of formula I or a pharmaceutically acceptable saltthereof, effective in treating such a condition.

[0079] The present invention also relates to a method for the inhibitionof protein typrosine kinases or Janus Kinase 3 (JAK3) in a mammal,including a human, comprising administering to said mammal an effectiveamount of a compound of formula I or a pharmaceutically acceptable saltthereof, alone or in combination with T-cell immunosuppressant orantiinflammatory agents.

[0080] The present invention also relates to a method for treating orpreventing a disorder or condition selected from organ transplantrejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis,Type I diabetes and complications from diabetes, cancer, asthma, atopicdermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn'sdisease, Alzheimer's disease, Leukemia, and other autoimmune diseases ina mammal, including a human, comprising administering to said mammal anamount of a compound of formula I or a pharmaceutically acceptable saltthereof, alone or in combination with T-cell immunosuppressant orantiinflammatory agents, effective in treating such a condition.

DETAILED DESCRIPTION OF THE INVENTION

[0081] The following reaction Schemes illustrate the preparation of thecompounds of the present invention. Unless otherwise indicated R¹, R²,R³ and R⁹ in the reaction Schemes and the discussion that follow aredefined as above.

[0082] In reaction 1 of Scheme 1, the 4-chloropyrrolo[2,3-d]pyrimidinecompound of formula XVII is converted to the corresponding compound offormula XVI, wherein R is benzenesulfonyl or benzyl, by treating XVIIwith benzenesulfonyl chloride, benzylchloride or benzylbromide in thepresence of a base, such as sodium hydride or potassium carbonate, and apolar aprotic solvent, such as dimethylformamide or tetrahydrofuran. Thereaction mixture is stirred at a temperature between about 0° C. toabout 70° C., preferably about 30° C., for a time period between about 1hour to about 3 hours, preferably about 2 hours.

[0083] In reaction 2 of Scheme 1, the 4-chloropyrrolo[2,3-d]pyrimidinecompound of formula XVI is converted to the corresponding4-aminopyrrolo[2,3-d]pyrimidine compound of formula XV by coupling XVIwith a compound of the formula R¹H. The reaction is carried out in analcohol solvent, such as tert-butanol, methanol or ethanol, or otherhigh boiling organic solvents, such as dimethylformamide, 1,4-dioxane or1,2-dichloroethane, at a temperature between about 60° C. to about 120°C., preferably about 80° C. Typical reaction times are between about 2hours to about 48 hours, preferably about 16 hours.

[0084] In reaction 3 of Scheme 1, removal of the protecting group fromthe compound of formula XV, wherein R is benzenesulfonyl, to give thecorresponding compound of formula I, is carried out by treating XV withan alkali base, such as sodium hydroxide or potassium hydroxide, in analcohol solvent, such as methanol or ethanol, or mixed solvents, such asalcoholltetrahydrofuran or alcohol/water. The reaction is carried out atroom temperature for a time period between about 15 minutes to about 1hour, preferably 30 minutes. Removal of the protecting group from thecompound of formula XV, wherein R is benzyl, is conducted by treating XVwith sodium in ammonia at a temperature of about −78° C. for a timeperiod between about 15 minutes to about 1 hour.

[0085] In reaction 1 of Scheme 2, the 4-chloropyrrolo[2,3-d]pyrimidinecompound of formula XXI, wherein R is hydrogen or benzenesulfonate, isconverted to the 4-chloro-5-halopyrrolo[2,3-d]pyrimidine compound offormula XX, wherein Y is chloro, bromo or iodo, by reacting XXI withN-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide. Thereaction mixture is heated to reflux, in chloroform, for a time periodbetween about 1 hour to about 3 hours, preferably about 1 hour.Alternatively, in reaction 1 of Scheme 2 the4-chloropyrrolo[2,3-d]pyrimidine of formula XXI, wherein R is hydrogen,is converted to the corresponding4-chloro-5-nitropyrrolo[2,3-d]pyrimidine of formula XX, wherein Y isnitro, by reacting XXI with nitric acid in sulfuric acid at atemperature between about −10° C. to about 10° C., preferably about 0°C., for a time period between about 5 minutes to about 15 minutes,preferably about 10 minutes. The compound of formula XXI, wherein Y isnitro, is converted to the corresponding4-chloro-5-aminopyrrolo[2,3-d]pyrimidine of the formula XX, wherein Y isamino, by reacting XXI under a variety of conditions known to oneskilled in the art such as palladium hydrogenolysis or tin(IV)chlorideand hydrochloric acid.

[0086] In reaction 2 of Scheme 2, the4-chloro-5-halopyrrolo[2,3-d]pyrimidine compound of formula XX, whereinR is hydrogen, is converted to the corresponding compound of formulaXIX, wherein R² is (C₁-C₆)alkyl or benzyl, by treating XX withN-butyllithium, at a temperature of about −78° C., and reacting thedianion intermediate so formed with an alkylhalide or benzylhalide at atemperature between about −78° C. to room temperature, preferably roomtemperature. Alternatively, the dianion so formed is reacted withmolecular oxygen to form the corresponding4-chloro-5-hydroxypyrrolo[2,3-d]pyrimidine compound of formula XIX,wherein R² is hydroxy. The compound of formula XX, wherein Y is bromineor iodine and R is benzenesulfonate, is converted to the compound offormula XIX, wherein R² is (C₆-C₁₂)aryl or vinyl, by treating XX withN-butyllithium, at a temperature of about −78° C., followed by theaddition of zinc chloride, at a temperature of about −78° C. Thecorresponding organo zinc intermediate so formed is then reacted witharyliodide or vinyl iodide in the presence of a catalytic quantity ofpalladium. The reaction mixture is stirred at a temperature betweenabout 50° C. to about 80° C., preferably about 70° C., for a time periodbetween about 1 hour to about 3 hours, preferably about 1 hour.

[0087] In reaction 3 of Scheme 2, the compound of formula XIX isconverted to the corresponding compound of formula XVI by treating XIXwith N-butyllithium, lithium diisopropylamine or sodium hydride, at atemperature of about −78° C., in the presence of a polar aproticsolvent, such as tetrahydrofuran. The anionic intermediate so formed isfurther reacted with (a) alkylhalide or benzylhalide, at a temperaturebetween about −78° C. to room temperature, preferably −78° C., when R³is alkyl or benzyl; (b) an aldehyde or ketone, at a temperature betweenabout −78° C. to room temperature, preferably −78° C., when R³ isalkoxy; and (c) zinc chloride, at a temperature between about −78° C. toroom temperature, preferably −78° C., and the corresponding organozincintermediate so formed is then reacted with aryliodide or vinyl iodidein the presence of a catalytic quantity of palladium. The resultingreaction mixture is stirred at a temperature between about 50° C. toabout 80° C., preferably about 70° C., for a time period between about 1hour to about 3 hours, preferably about 1 hour. Alternatively, the anionso formed is reacted with molecular oxygen to form the corresponding4-chloro-6-hydroxypyrrolo[2,3-d]pyrimidine compound of formula XVI,wherein R³ is hydroxy.

[0088] In reaction 1 of Scheme 3, the 4-chloropyrrolo[2,3-d]pyrimidinecompound of formula XXI is converted to the corresponding compound offormula XXII, according to the procedure described above in reaction 3of Scheme 2.

[0089] In reaction 2 of Scheme 3, the compound of formula XXII isconverted to the corresponding compound of formula XVI, according to theprocedures described above in reactions 1 and 2 of Scheme 3.

[0090] In reaction 1 of Scheme 4, the 4-chloropyrrolo[2,3-d]pyrimidinecompound of formula XX is converted to the corresponding4-aminopyrrolo[2,3-d]pyrimidine compound of formula XXIV, according tothe procedure described above in reaction 2 of Scheme 1.

[0091] In reaction 2 of Scheme 4, the4-amino-5-halopyrrolo[2,3-d]pyrimidine compound of formula XXIV, whereinR is benzenesulfonate and Z is bromine or iodine, is converted to thecorresponding compound of formula XXIII by reacting XXIV with (a)arylboronic acid, when R² is aryl, in an aprotic solvent, suchtetrahydrofuran or dioxane, in the presence of a catalytic quantity ofpalladium (0) at a temperature between about 50° C. to about 100° C.,preferably about 70° C., for a time period between about 2 hours toabout 48 hours, preferably about 12 hours; (b) alkynes, when R² isalkynyl, in the presence of a catalytic quantity of copper (I) iodideand palladium (0), and a polar solvent, such as dimethylformamide, atroom temperature, for a time period between about 1 hour to about 5hours, preferably about 3 hours; and (c) alkenes or styrenes, when R² isvinyl or styrenyl, in the presence of a catalytic quantity of palladiumin dimethylformamide, dioxane or tetrahydrofuran, at a temperaturebetween about 80° C. to about 100° C., preferably about 100° C., for atime period between about 2 hours to about 48 hours, preferably about 48hours.

[0092] In reaction 3 of Scheme 4, the compound of formula XXIII isconverted to the corresponding compound of formula XV, according to theprocedure described above in reaction 3 of Scheme 2.

[0093] The compounds of the present invention that are basic in natureare capable of forming a wide variety of different salts with variousinorganic and organic acids. Although such salts must bepharmaceutically acceptable for administration to animals, it is oftendesirable in practice to initially isolate the compound of the presentinvention from the reaction mixture as a pharmaceutically unacceptablesalt and then simply convert the latter back to the free base compoundby treatment with an alkaline reagent and subsequently convert thelatter free base to a pharmaceutically acceptable acid addition salt.The acid addition salts of the base compounds of this invention arereadily prepared by treating the base compound with a substantiallyequivalent amount of the chosen mineral or organic acid in an aqueoussolvent medium or in a suitable organic solvent, such as methanol orethanol. Upon careful evaporation of the solvent, the desired solid saltis readily obtained. The desired acid salt can also be precipitated froma solution of the free base in an organic solvent by adding to thesolution an appropriate mineral or organic acid.

[0094] Those compounds of the present invention that are acidic innature, are capable of forming base salts with various pharmacologicallyacceptable cations. Examples of such salts include the alkali metal oralkaline-earth metal salts and particularly, the sodium and potassiumsalts. These salts are all prepared by conventional techniques. Thechemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the acidic compounds of the presentinvention. Such non-toxic base salts include those derived from suchpharmacologically acceptable cations as sodium, potassium calcium andmagnesium, etc. These salts can easily be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction and maximum yields of the desired final product.

[0095] The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptable,carriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.., intravenous,intramuscular or subcutaneous) or rectal administration or in a formsuitable for administration by inhalation or insufflation. The activecompounds of the invention may also be formulated for sustaineddelivery.

[0096] For oral administration, the pharmaceutical compositions may takethe form of, for example, tablets or capsules prepared by conventionalmeans with pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinized maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g., magnesium stearate,talc or silica); disintegrants (e.g., potato starch or sodium starchglycolate); or wetting agents (e.g., sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters or ethyl alcohol); and preservatives(e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

[0097] For buccal administration, the composition may take the form oftablets or lozenges formulated in conventional manner.

[0098] The active compounds of the invention may be formulated forparenteral administration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g, in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

[0099] The active compounds of the invention may also be formulated inrectal compositions such as suppositories or retention enemas, e.g.,containing conventional suppository bases such as cocoa butter or otherglycerides.

[0100] For intranasal administration or administration by inhalation,the active compounds of the invention are conveniently delivered in theform of a solution or suspension from a pump spray container that issqueezed or pumped by the patient or as an aerosol spray presentationfrom a pressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

[0101] A proposed dose of the active compounds of the invention fororal, parenteral or buccal administration to the average adult human forthe treatment of the conditions referred to above (e.g., asthma) is 0.1to 1000 mg of the active ingredient per unit dose which could beadministered, for example, 1 to 4 times per day.

[0102] Aerosol formulations for treatment of the conditions referred toabove (e.g., rheumatoid arthritis) in the average adult human arepreferably arranged so that each metered dose or “puff” of aerosolcontains 20 μg to 1000 μg of the compound of the invention. The overalldaily dose with an aerosol will be within the range 0.1 mg to 1000 mg.Administration may be several times daily, for example 2, 3, 4 or 8times, giving for example, 1, 2 or 3 doses each time.

[0103] A compound of formula (I) administered in a pharmaceuticallyacceptable form either alone or in combination with one or moreadditional agents which modulate a mammlian immune system or withantiinflammatory agents, agents which may include but are not limited tocyclosporin A (e.g. Sandimmune® or Neoral®, rapamycin, FK-506(tacrolimus), leflunomide, deoxyspergualin, mycophenolate (e.g.Cellcept®, azathioprine (e.g. Imuran®), daclizumab (e.g. Zenapax®), OKT3(e.g. Orthocolone®), AtGam, aspirin, acctaminophen, ibuprofen, naproxen,piroxicam, and antiinflammatory steroids (e.g. prednisolone ordexamethasone); and such agents may be administered as part of the sameor separate dosage forms, via the same or different routes ofadministration, and on the same or different administration schedulesaccording to standard pharmaceutical practice.

[0104] FK506 (Tacrolimus) is given orally at 0.10-0.15 mg/kg bodyweight, every 12 hours, within first 48 hours postoperative. Does ismonitored by serum Tacrolimus trough levels.

[0105] Cyclosporin A (Sandimmune oral or intravenous formulation, orNeoral®, oral solution or capsules) is given orally at 5 mg/kg bodyweight, every 12 hours within 48 hours postoperative. Dose is monitoredby blood Cyclosporin A trough levels.

[0106] The active agents can be formulated for sustained deliveryaccording to methods well known to those of ordinary skill in the art.Examples of such formulations can be found in U.S. Pat. Nos. 3,538,214,4,060,598, 4,173,626, 3,119,742, and 3,492,397.

[0107] The ability of the compounds of formula I or theirpharmaceutically acceptable salts to inhibit Janus Kinase 3 and,consequently, demonstrate their effectiveness for treating disorders orconditions characterized by Janus Kinase 3 is shown by the following invitro assay tests.

Biological Assay JAK3 (JH1:GST) Enzymatic Assay

[0108] The JAK3 kinase assay utilizes a protein expressed inbaculovirus-infected SF9 cells (a fusion protein of GST and thecatalytic domain of human JAK3) purified by affinity chromatography onglutathione-Sepaharose. The substrate for the reaction is poly-Glutamicacid-Tyrosine (PGT (4:1), Sigma catalog # P0275), coated onto Nunc MaxiSorp plates at 100 μg/ml overnight at 37° C. The morning after coating,the plates are washed three times and JAK3 is added to the wellscontaining 100 μl of kinase buffer (50 mM HEPES, pH 7.3, 125 mM NaCl, 24mM MgCl2)+0.2 uM ATP+1 mM Na orthovanadate.) The reaction proceeds for30 minutes at room temperature and the plates is washed three moretimes. The level of phosphorylated tyrosine in a given well isquantitated by standard ELISA assay utilizing an anti-phosphotyrosineantibody (ICN PY20, cat. #69-151-1).

DND 39/IL-4 Cellular Assay for JAK3 Kinase Inhibitors

[0109] The DND 39/IL-4 assay is designed to find inhibitors of JAK3kinase activity which would be prime candidates for immunosupressiveand/or allergy. The assay uses a B-cell line called DND39 which has hadthe luciferase gene driven by the germ line IgE promoter stablyintegrated into one of the chromosomes. When these cells are stimulatedwith IL-4, the kinase JAK3, which is associated with the IL-4 receptor,phosphorylates the signal transducer STAT6. STAT6 then blinds to thegermline IgE promoter and starts transcription of the luciferase gene.Luciferase is measured in a lysate of these cells using the Promegaluciferase assay reagent system.

[0110] Note: DND39 cells are grown in RPMI 1640 supplemented with 10%heat inactivated FCS, 2 mM L-Glutamine, and 100 units/ml Pen./Strep. Thecells are maintained from 1×10⁵ to 1×10⁶ cells/ml. Split to 1×10⁵ onFriday, cells will be at about 1×10⁶ on Monday. Then split 1:2 duringthe week keeping 200 ml in a flask as needed.

[0111] 3×10⁵ DND39 cells are plated in 100 μl of RPMI 1640 supplementedwith 1% heat inactivated FCS, 2 mM L-glutamine, and 100 units/mlPen/Step in a 96 well Vee bottom plate (Nunc). Compounds are dilutedserially 1:2 in DMSO starting at 4mM to 1.9 μM. In a 96 wellpolypropylene plate, changing tips after each dilution. Then 5 μl ofeach dilution are added to 500 μl of RPMI/1% serum in a 96 tube rack.125 μL of the compound dilutions are added to the cells and incubated at37° C., 5% CO₂ for one hour. After one hour, 25 μl of 25 ng/ml IL-4 isadded to the cells and mixed. Final concentration of IL-4 is 2.5 ng/mland final concentration of compound is from 20 μM to 156 nM. The cellsare then incubated overnight 16-18 hours. The plate is then centrifugedat 2500-3000 RPM in a table top centrifuge for 5 minutes. The culturesupernatant is carefully removed by aspiration with an 8 well maifold.100 μl of PBS with calcium and magnesium is added to the pellettedcells. The cells are resuspended in the PBS and transferred to a Packardwhite OptiPlate. 100 μl of Packard's LucLite reagent is added to thewells of the OptiPlate.

[0112] The following Examples illustrate the preparation of thecompounds of the present invention but it is not limited to the detailsthereof. Melting points are uncorrected. NMR data are reported in partsper million (δ) and are referenced to the deuterium lock signal from thesample solvent (deuteriochloroform unless otherwise specified).Commercial reagents were utilized without further purification. THFrefers to tetrahydrofuran. DMF refers to N,N-dimethylformamide. LowResolution Mass Spectra (LRMS) were recorded on either a Hewlett Packard5989®, utilizing chemical ionization (ammonium), or a Fisons (or MicroMass) Atmospheric Pressure Chemical Ionization (APCI) platform whichuses a 50/50 mixture of acetonitrile/water with 0.1% formic acid as theionizing agent. Room or ambient temperature refers to 20-25° C.

EXAMPLE 1 Cyclohexyl-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amineMethod A Cyclohexyl-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

[0113] A mixture of 200 mg (1.30 mmol) of4-chloro-7H-pyrrolo[2,3-d]pyrimidine (prepared by the method of Davoll,J. Am. Chem. Soc., (1960), 82, 131), the product from Method A (589mg/5.21 mmol) and 3 mL of tert-butanol was stirred in a sealed tube at100° C. for 24 hours. The reaction mixture was added to water, acidifiedto pH 1 with 1 N hydrochloric acid (aq), washed twice with diethylether(ether) and basified to pH 14 with 1 N sodium hydroxide (NaOH). Theresulting precipitate was filtered and dried in vacuo to obtain 263 mg(88%) of the title compound, mp 177-180° C. ¹H NMR (400 MHz, CDCl₃): δ1.11-1.22 (m, 1H), 1.43-1.63 (m, 4H), 1.73 (br d, 1H, J=13.3 Hz),1.83-1.90 (m, 4 H), 3.23 (s, 3H), 4.69 (br, 1H), 6.53 (d, 1H, J=3.5 Hz),7.03 (d, 1H, J=3.5 Hz), 8.30 (s, 1H), 10.6 (br, 1H). LRMS: 231 (M+1).

[0114] The title compounds of Examples 2-51 were prepared by a methodanalogous to that described in Example 1.

EXAMPLE 29-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-2,3,4,4a,9,9a-hexahydro-1H-carbazoleEXAMPLE 3 4-(2,6-Dimethyl-morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0115] 2,6-Dimethylmorpholine. LRMS: 233.3.

EXAMPLE 4 4-Morpholin-4-yl-7H-pyrrolo[2,3-d]pyrimidine

[0116] 4-Morpholine. LRMS: 205.

EXAMPLE 5 4-(2,5-Dimethyl-pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0117] 2,5-Dimethylpyrrolidine. Melting Point: 227-229° C.; LRMS: 216.3.

EXAMPLE 6 4-(4-Benzyl-piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0118] 4-Benzylpiperidine. Melting Point: 188-190° C.; LRMS: 292.4.

EXAMPLE 7 4-Phenyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ol

[0119] 4-Phenylpiperidin-4-ol. Melting Point: 201-202° C.; LRMS: 294.4.

EXAMPLE 81-[1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

[0120] Piperidin-4-yl-1,3-dihydrobenzoimidazole. Melting Point: 182-184°C.; LRMS: 334.4.

EXAMPLE 91-Phenyl-8-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3,8-triaza-spiro[4.5]decan-4-one

[0121] 1-Phenyl-1,3,8-triaza-spiro[4.5]decan4-one. Melting Point:232-234° C.

EXAMPLE 10 4-(3-Methyl-piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0122] 3-Methylpiperidine. Melting Point: 176-178° C.; LRMS: 217.1.

EXAMPLE 11 4-(3,5-Dimethyl-piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0123] 3,5-Dimethylpiperidine. Melting Point: 258-260° C.; LRMS: 231.

EXAMPLE 12 4-(2-Methyl-piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0124] 2-Methyl-piperidine. Melting Point: 144-146° C.; LRMS: 217.1.

EXAMPLE 13 4-(2-Ethyl-piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0125] 2-Ethylpiperidine. Melting Point: 112-114° C.; LRMS: 231.

EXAMPLE 14 [1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-2-yl]-methanol

[0126] Piperidine-2-yl-methanol. Melting Point: 135-136° C.; LRMS:232.9.

EXAMPLE 15 1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-3-carboxylicacid diethylamide

[0127] Piperidine-3-carboxylic acid diethylamide. LRMS: 302.1.

EXAMPLE 162-[1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-2-yl]-ethanol

[0128] Piperidin-2-yl-ethanol. Melting Point: 139-140° C.

EXAMPLE 17 4-Azocan-1-yl-7H-pyrrolo[2,3-d]pyrimidine

[0129] Azapane. Melting Point: 225-226° C.; LRMS: 231.3.

EXAMPLE 18 1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-3-carboxylicacid amide

[0130] Piperidine-3-carboxylic acid amide. Melting Point: 283-285° C.

EXAMPLE 19Dimethyl-[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrrolidin-3-yl]-amine

[0131] Dimethylpyrrolidin-3-yl-amine. Melting Point: 210-212° C.; LRMS:232.2.

EXAMPLE 20N-Ethyl-N-[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrrolidin-3-yl]-acetamide

[0132] N-Ethylpyrrolidin-3-yl-acetamide. Melting Point: 197-199° C.;LRMS: 274.3.

EXAMPLE 214-(2-Methoxymethyl-pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0133] 2-Methoxymethylpyrrolidine. Melting Point: 134-135° C.; LRMS:233.2.

EXAMPLE 22[1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-pyrrolidin-2-yl]-methanol

[0134] Pyrrolidin-2-yl-methanol. Melting Point: 188-189° C.; LRMS:219.3.

EXAMPLE 23N-[1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-pyrrolidin-3-yl]-acetamide

[0135] Pyrrolidin-3-yl-acetamide. Melting Point: 260-261° C.; LRMS:246.3.

EXAMPLE 24 4-(2-Propyl-piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0136] Propylpiperidine. Melting Point: 106-107° C.; LRMS: 245.3.

EXAMPLE 25 4-(4-Methyl-piperazin-1-yl)-7H-pyrrol[2,3-d]pyrimidine

[0137] 4-Methylpiperazine. Melting Point: 141-142° C.

EXAMPLE 26 4-Piperazin-1-yl-7H-pyrrolo[2,3-d]pyrimidine

[0138] Piperazine. Melting Point: 164-166° C.

EXAMPLE 27 4-Azepan-1-yl-7H-pyrrolo[2,3-d]pyrimidine

[0139] Azapane. Melting Point: 210° C.; LRMS: 217.3.

EXAMPLE 28 1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-pyrrolidin-3-ol

[0140] Pyrrolidin-3-ol. Melting Point: 220-225° C.; LRMS: 205.2.

EXAMPLE 29 [1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-3-yl]-methanol

[0141] Piperidine-3-yl-methanol. Melting Point: 161.5-163.5° C.; LRMS:234.3.

EXAMPLE 30 1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylicacid ethyl ester

[0142] Piperidine-4-carboxylic acid ethyl ester. Melting Point: 139-141°C.; LRMS: 275.3.

EXAMPLE 31 1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-3-carboxylicacid ethyl ester

[0143] Piperidine-3-carboxylic acid ethylester. Melting Point: 139.5-141.5° C.; LRMS: 275.3.

EXAMPLE 322-[1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-ethanol

[0144] Piperidin-4-yl-ethanol. Melting Point: 129-131° C.; LRMS: 265.3.

EXAMPLE 33 4-(4-Phenyl-piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0145] 4-Phenylpiperidine. Melting Point: 195° C.; LRMS: 279.

EXAMPLE 344-(4-Trifluoromethyl-piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0146] 4-Trifluoromethylpiperidine. Melting Point: 198° C.; LRMS: 271.

EXAMPLE 354-[4-(3-Phenyl-propyl)-piperidin-1-yl]1-7H-pyrrolo[2,3-d]pyrimidine

[0147] 4-(3-Phenylpropyl)piperidine. Melting Point: 134° C.; LRMS: 321.

EXAMPLE 36 4-(3,3-Dimethyl-piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0148] 3,3-Dimethylpiperidine. Melting Point: 204° C.; LRMS: 231.

EXAMPLE 37 1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-3-carboxylicacid

[0149] Piperidine-3-carboxylic acid. Melting Point: 159-160° C.; LRMS:307.3.

EXAMPLE 38 1-M thyl-10-oxa-4-aza-tricyclo[5.2.1.0%2,6&]decane

[0150]1-Methyl-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-10-oxa-4-aza-tricyclo[5.2.1]decane.Melting Point: 251-252° C.; LRMS: 271.3.

EXAMPLE 391-(5-Chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-decahydro-quinoline

[0151] Decahydroquinoline. Melting Point: 190-192° C.; LRMS: 291.8.

EXAMPLE 403-[1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-3-yl]-propionic acidethyl ester

[0152] Piperidin-3-yl-propionic acid ethyl ester. Melting Point: 101-103° C.; LRMS: 303.4.

EXAMPLE 413-[1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-3-yl]-propionic acid

[0153] Piperidine-3-yl-propionic acid. Melting Point: 217-219° C.; LRMS:275.3.

EXAMPLE 42 1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-3-ol

[0154] Piperidin-3-ol. Melting Point: 152-154° C.; LRMS: 219.3.

EXAMPLE 433-[1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-3-yl]-propionamide

[0155] Piperidin-3-yl-propionamide. Melting Point: 212-214° C.; LRMS:274.3.

EXAMPLE 44 4-(2,6-Dimethyl-piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0156] 2,6-Dimethylpiperidine. LRMS: 231.

EXAMPLE 452-[1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-3-yl]-propan-2-ol

[0157] Piperidin-3-yl-propan-2-ol. Melting Point: 182.8-183.6° C.; LRMS:261.

EXAMPLE 462-[1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-propan-2-ol

[0158] Piperidin-4-yl-propan-2-ol. Melting Point: 170.1-171.3° C.; LRMS:261.

EXAMPLE 47 4-Methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ol

[0159] 4-Methylpiperdin4-ol. Melting Point: 163.8-165.1° C.; LRMS:233.1.

EXAMPLE 483-Methyl-8-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-8-aza-bicyclo[3,2,1]octan-3-ol

[0160] 3-Methyl-8-aza-bicyclo[3,2,1]octan-3-ol. Melting Point:142.1-143.8° C.; LRMS: 259.1.

EXAMPLE 49 2-[1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-pyrrolidin-2-yl]-prpan-2-ol

[0161] Pyrrolidin-2-yl-propan-2-ol. Melting Point: 173 dec; LRMS: 247.1.

EXAMPLE 50 3-Methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrrolidin-3-ol

[0162] 3-Methylpyrrolidin-3-ol. LRMS: 219.

EXAMPLE 51 4-Pyrazol-1-yl-7H-pyrrolo[2,3-d]pyrimidine

[0163] Pyrazole. LRMS: 186.2.

EXAMPLE 52Cyclohexyl-methyl-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

[0164] Cyclohexylmethylamine.

Method B 7-Benzenesulfonyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidine

[0165] In a flame-dried flask under nitrogen, 780 mg of 60% sodiumhydride ( 19.5 mmol) in mineral oil was added to 30 mL ofdimethylformamide (DMF) and the resulting mixture cooled to 0° C. Asolution of 2.0 g (13.0 mmol) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine in10 mL of DMF was added slowly over a 5 minute period. The reaction wasstirred for 10 min at which time generation of hydrogen (H₂) ceased.Benzenesulfonylchloride (1.7 mL/13.0 mmol) was added, the reactionwarmed to room temperature and stirred for 1 hour. Water was added, andthe resulting precipitate was filtered and dried in vacuo to obtain 3.4grams (89%) of the title compound as a crystalline solid, mp 163-167° C.

Method C 7-Benzenesulfonyl-4-chloro-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine

[0166] In a flame-dried flask under nitrogen, 0.53 mL (3.79 mmol) ofdiisopropylamine were dissolved in 5 mL of tetrahydrofuran (THF) and thesolution cooled to −78° C. n-Butyllithium (3.75 mmol as a 2.5 M solutionin hexanes) was added and the resulting mixture brought to 0° C. withcontinued stirring for 10 minutes. The reaction mixture was again cooledto −78° C. and to this mixture added a solution of 1.0 grams (3.40 mmol)of the product from Method B in 10 mL of THF over a 10 min period. Thereaction mixture was stirred for 1 hour at −78° C., at which time, 8.2mL (4.10 mmol) of a 0.5 M solution of zinc chloride in THF was added,the reaction mixture was brought to room temperature and stirred for 1hour. lodobenzene (0.46 mL/4.11 mmol) and a suspension of 197 mg oftetrakis(triphenylphosphine) palladium in 2 mL of THF were added. Theresulting mixture was stirred at reflux for 3 hours, cooled to roomtemperature, and partitioned between dichloromethane and water. Theaqueous layer was acidified with 1 N HCl and extracted twice withdichloromethane. The dichloromethane layers were combined, washed with 1N HCl and brine, dried over magnesium sulfate (MgSO₄), filtered andconcentrated in vacuo to obtain the title compound. LRMS: 370, 372(M+2).

Method D 4-Chloro-6-phenyl-7H-pyrr l [2,3-d]pyrimidine

[0167] The product from Method C was dissolved in 10 mL of THF and tothis solution was added 5.0 mL of methanol and 1.0 grams of NaOH. Thereaction mixture was stirred for 15 minutes, concentrated in vacuo andpartitioned between a saturated aqueous solution of ammonium chloride(NH₄Cl) and ethyl acetate. . The resulting aqueous layer was extractedtwice with ethyl acetate. The ethylacetate layers were combined, washedwith brine, dried over MgSO₄, filtered and concentrated in vacuo. Thecrude product was purified by silica-gel chromatography (1:5 ethyl-acetate/hexane) to obtain 0.59 grams (76%) of the title compound as apale yellow solid, mp 145° C. (dec). LRMS: 230, 232 (M+2).

Method ECyclohexyl-methyl-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

[0168] The product from Method D (50 mg/0.218 mmol) was reacted with0.12 mL of N-methylcyclohexylamine (0.920 mmol) as described in MethodA. The reaction mixture was concentrate in vacuo, methanol was added,and the resulting precipitate filtered to provide 7 mg (10%) of thetitle compound as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ: 1.18-1.25(m, 1H), 1.47-1.66 (m, 4H), 1.75-1.90 (m, 5H), 3.30 (s, 3H), 4.74 (br,1H), 6.79 (s, 1H), 7.32-7.36 (m, 1H), 7.47-7.51 (m, 2H), 7.77 (d, 2H,J=7.9 Hz), 8.33 (s, 1H). LRMS: 307 (M+1).

[0169] The title compounds of Examples 53-58 were prepared by a methodanalogous to that described in Example 52.

EXAMPLE 531-(6-Phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-decahydro-quinoline

[0170] Decahydroquinoline. LRMS: 333.4.

EXAMPLE 544-(2-Ethyl-piperidin-1-yl)-6-Phenyl-7H-pyrrolo[2,3-d]pyrimidine

[0171] 2-Ethylpiperidine. LRMS: 307.4.

EXAMPLE 554-(3,3-Dimethyl-piperidin-1-yl)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine

[0172] 3,3-Dimethylpiperidine. LRMS: 307.4.

EXAMPLE 56 6-Phenyl-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine

[0173] Piperidine. LRMS: 279.4.

EXAMPLE 57 4-Piperidin-1-yl-6-thiophen-3-yl-7H-pyrrolo[2,3-d]pyrimidine

[0174] Piperidine. LRMS: 285.4.

EXAMPLE 58 4-Piperidin-1-yl-6-thiophen-2-yl-7H-pyrrolo[2,3-d]pyrimidine

[0175] Piperidine. LRMS: 285.4.

EXAMPLE 59Cyclohexyl-methyl-(6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

[0176] Cyclohexylmethylamine.

Method F 7-Benzenesulfonyl-4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine

[0177] To flame-dried flask under N₂ was charged 0.57 ml (4.07 mmol) ofdiisopropylamine and 5.0 mL of dry THF. The solution was cooled to −78°C. and 1.63 mL (4.08 mmol) of a 2.5 M solution of n-butyllithium inhexanes added. The resulting mixture was brought to 0° C. and stirredfor 10 minutes. After cooling the mixture again to −78° C., a solutionof 1.0 g (3.40 mmol) of crude product from Method C in 10 mL of dry THFwas added over a 10 minute period. The resulting mixture was stirred for1 hour, at which time, 0.28 mL (4.50 mmol) of iodomethane were added.The reaction mixture was stirred for 2 hours, quenched with a saturatedsolution of NH₄Cl and warmed to room temperature. The mixture wasstirred for 5 minutes, diluted with water and extracted three times withethyl acetate. The combined extracts were washed with brine, dried overMgSO₄, filtered and evaporated in vacuo to obtain the title compound.LRMS: 308, 310 (M+2).

Method G 4-Chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine

[0178] The product from Method F was deprotected as described in MethodE. The crude product was purified by trituration with hexanes anddichloromethane to obtain 250 mg (44%) of the title compound as a yellowsolid. Mp 205° C. dec. LRMS 168, 170 (M+2).

Method HCyclohexyl-methyl-(6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

[0179] The product from Method G (50 mg/0.298 mmol) was reacted with 100mg (0.883 mmol) of N-methylcyclohexylamine as described in Method A. Thereaction mixture was worked up as in Method A with the exception thatethyl acetate was used in place of ether. The title compound (42 mg, 58%yield) was obtained as a white solid. Mp 221° C. dec. ¹H NMR (400 MHz,CDCl₃) δ: 1.15-1.25 (m, 1H), 1.43-1.62 (m, 4H), 1.73 (br s, 1H, J=13.7Hz), 1.82-1.90 (m, 4H), 2.41 (d, 3H, J=0.8 Hz), 3.21 (s, 3H) 4.63 (br s,1H), 6.20 (s, 1H), 8.22 (s, 1H), 10.1 (br s, 1H). LRMS: 245 (M+1).

[0180] The title compound of Example 60 was prepared by a methodanalogous to that described in Example 59.

EXAMPLE 60 6-Methyl-4-piperidin-1-yl-7H-Pyrrolo[2,3-d]pyrimidine

[0181] Piperidine. LRMS: 217.3.

EXAMPLE 61 5-Chloro-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine MethodI 4,5-Dichloro-7H-pyrrolo[2,3-d]pyrimidine

[0182] 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (154 mg, 1.0 mmol) wassuspended in 6.0 mL of dry dichloromethane in a flame-dried flask and tothis mixture was added N-chlorosuccinimide (147 mg, 1.1 mmol) in oneportion. The resulting mixture stirred at room temperature for 18 h, atwhich time the solvent was removed under reduced pressure. The residuewas triturated with water and isolated by filtration to afford 137 mg(72%) of the title compound as a gray solid, mp 224-227° C.(dec). LRMS:188 (M+1).

Method J 5-Chloro-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine

[0183] The product from Method I (57 mg, 0.3 mmol) was suspended in 3.0mL of tert-butanol and to this solution was added piperidine (90 μL, 0.9mmol) and the resulting system heated at reflux for 1 hour. The reactionmixture was cooled to room temperature and water was added (4.0 mL). Thesolution was adjusted to pH 1 with 1 N HCl and then washed with ether.The aqueous layer was removed and adjusted to pH 12 with 2 N NaOH. Thesolution was then extracted 2×15 mL with dichloromethane and thecombined organics washed with water then brine and dried over MgSO₄.Evaporation of solvent afforded 45 mg of a yellow solid that waspurified by silica-gel chromatography (3:1 ethyl acetate/hexanes) toyield 23 mg (32%) of the title compound as a light yellow solid. Mp170-172° C. ¹H NMR (400 MHz, CDCl₃) δ: 1.67-1.74 (m, 6H), 3.65-3.67 (m,4H), 7.10 (s, 1H), 8.31 (s, 1H). LRMS: 237 (M+1).

[0184] The title compounds of Examples 62-63 were prepared by a methodanalogous to that described in Example 61.

EXAMPLE 62 5-Chloro-4-(octahydro-indol-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0185] Octahydroindole. Melting Point: 193° C.; LRMS: 277.8.

EXAMPLE 631-(5-Chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-decahydro-quinoline

[0186] Decahydroquinoline. Melting Point: 190-192° C.; LRMS: 291.8.

EXAMPLE 64 5-Phenyl-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine MethodK 5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine

[0187] To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (30g/0.02 mol) dissolved in 75 mL of chloroform was added 3.5 grams (0.02mol) of N-bromosuccinamide and the resulting mixture refluxed for 1hour. After cooling to room temperature, the precipitate was removed byfiltration and dried under reduced pressure affording 4.1 grams (89%) ofthe title compound. ¹H NMR (400 MHz) (CDCl₃) δ: 7.93 (d, 1H, J=2.8 Hz),8.60 (s, 1H).

Method L 7-Benzenesulfonyl-5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine

[0188] To a slurry of the product from Method K (4.1 g/0.018 mol) in DMF(15 mL) and cooled to 0° C. was added 1.0 g (0.025 mol) of 60% sodiumhydride in mineral oil and the resulting mixture stirred at 0° C. for 15minutes. Benzenesulfonyl chloride (3.2 g/0.018 mol) was added, thereaction mixture warmed to room temperature and stirred for 2 hours.Water was then added (15 mL) and the resulting solid removed byfiltration and dried in vacuo affording 5.9 grams (89%) of the titlecompound.

Method M7-Benzenesulfonyl-5-bromo-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine

[0189] A mixture of 2.0 g (5.37 mmol) of the product from Method L and1.1 grams (13.4 mmol) of piperidine in 10 mL of tert-butanol was heatedwith stirring at 60° C. for 2 hours. After cooling to room temperature,the reaction mixture was partitioned between dichloromethane (25 mL) andwater (25 mL). The dichloromethane layer was dried over sodium sulfate(Na₂SO₄) and concentrated to dryness in vacuo affording 2.2 grams (97%)of the title compound. ¹H NMR (400 MHz) (CDCl₃) δ: 1.63-1.72 (m, 6H),3.54-3.57 (m, 4H), 7.53 (t, 2H, J=2.0 Hz), 7.60 (s,1 H), 7.61 (t, 1 H,J=2.0 Hz), 8.17-8.20 (m, 2H), 8.43 (s, 1 H). LRMS: 422.7, 420.7 (M+1).

Method N 5-Phenyl-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine

[0190] To a stirred solution of the product from Method M (100 mg/0.237mmol) in 1.0 mL of dioxane was added 32 mg (0.261 mmol) of phenylboronicacid and 75 mg (0.356 mmol) of tribasic potassium phosphate followed by7 mg (0.006 mmol) of tetrakis(triphenylphosphine) palladium. Theresulting mixture was degassed with nitrogen and stirred at 100° C. for48 hours. After cooling to room temperature, 1.0 mL of methanol wasadded followed by 50 mg of NaOH and the new mixture stirred at roomtemperature for 1 hour. The resulting mixture was then partitionedbetween dichloromethane and water, the dichloromethane layer dried overMgSO₄ and concentrated to dryness in vacuo. The crude product waspurified by silica-gel chromatography (2:1 ethyl acetate/hexanes)affording 13 mg ( 20%) of the title compound. ¹H NMR (400 MHz) (CDCl₃)δ: 1.33-1.34 (m, 4H), 1.43-1.44 (m, 2H), 3.26-3.28 (m, 4H), 7.12 (s,1H), 7.27 (t, 1H, J =7.2 Hz), 7.38 (t, 2H, J =8.0 Hz), 7.45 (d, 2H, J=0.8 Hz), 8.42 (s, 1 H). LRMS: 279.2 (M+1).

[0191] The title compounds of Examples 65-77 were prepared by a methodanalogous to that described in Example 64.

EXAMPLE 655-(3-Chloro-4-fluoro-phenyl)-4-piperidin-1-yl-7H-pyrrol[2,3-d]pyrimidin

[0192] Piperidine. LRMS: 331.8.

EXAMPLE 665-(4-Fluoro-phenyl)-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine

[0193] Piperidine. LRMS: 297.

EXAMPLE 675-(4-Chloro-phenyl)-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine

[0194] Piperidine. LRMS: 313.

EXAMPLE 685-(3,5-Bis-trifluoromethyl-phenyl)-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine

[0195] Piperidine. LRMS: 415.4.

EXAMPLE 69 4-Piperidin-1-yl-5-o-tolyl-7H-pyrrolo[2,3-d]pyrimidine

[0196] Piperidine. LRMS: 293.4.

EXAMPLE 70 4-Piperidin-1-yl-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidine

[0197] Piperidine. LRMS: 293.4.

EXAMPLE 715-(4-Methoxy-phenyl)-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine

[0198] Piperidine. LRMS: 309.4.

EXAMPLE 724-Piperidin-1-yl-5-(3-trifluoromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidine

[0199] Piperidine. LRMS: 347.4.

EXAMPLE 735-(3-Chloro-phenyl)-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine

[0200] Piperidine. LRMS: 427.8.

EXAMPLE 74 3-(4-Piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-benzoicacid ethyl ester

[0201] Piperidine. LRMS: 465.4.

EXAMPLE 752-[3-(4-Piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-phenyl]-propan-2-ol

[0202] Piperidine. LRMS: 451.4.

EXAMPLE 764-(2-Methyl-piperidin-1-yl)-5-m-tolyl-7H-pyrrolo[2,3-d]pyrimidine

[0203] 2-methyl-piperidine. LRMS: 307.2.

EXAMPLE 77 4-Azepan-1-yl-5-m-tolyl-7H-pyr lo[2,3-d]pyrimidine

[0204] Azepane. LRMS: 307.2.

EXAMPLE 78 Method O 4-Piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile

[0205] To a stirred solution of4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (54 mg/0.3 mmol)(prepared by the method of Townsend, et. al., J. Am. Chem. Soc., 1969,91, 2102) suspended in 3.0 mL tert-Butanol was added piperidine (59μL/0.60 mmol). The resulting mixture was then heated at reflux for 2.5 hand after cooling to room temperature, was transferred to a separatoryfunnel and diluted with ether (20 mL). The solution was extracted 2×10mL with 1N HCl, the combined aqueous layers were adjusted to pH 7 with 2N potassium hydroxide (KOH) solution forming a precipitate which wascollected by filtration, washed with water and dried under reducedpressure to give 29 mg (42%) of the title compound as a colorless solid.Mp 209-211° C.; ¹H NMR (400 MHz) (acetone-d6) δ: 1.72-1.74 (m, 6H),3.72-3.79 (m, 4H), 8.12 (s, 1 H), 8.29 (s, 1 H). LRMS: 228 (M+1).

EXAMPLE 79 5-Ethynyl-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine MethodP 4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

[0206] To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (30g/0.02 mol) dissolved in 80 mL of chloroform was added 4.5 grams (0.02mol) of N-iodosuccinimide and the resulting mixture heated at reflux for1 hour. After cooling to room temperature, the percipitate was removedby flitration and dried under reduced pressure affording 4.6 grams (82%)of the title compound.

Method Q 7-Benzenesulfonyl-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

[0207] The title compound was prepared as previously described in MethodL using the product from Method O affording 5.4 grams (80%) of material.LRMS: 419.6 (M+1), 279.7.

Method R7-Benzenesulfonyl-5-iodo-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine

[0208] The title compound was prepared by the procedure described inMethod M using the product from Method Q to produce the title compound.LRMS: 469 (M+1), 329.1.

Method S7-Benzenesulfonyl-4-piperidin-1-yl-5-triethylsilanylethynyl-7H-pyrrolo[2,3-d]pyrimidine

[0209] To a flamed-dried flask under nitrogen was charged 211 mg (0.5mmol) of the product from Method R, 19 mg (0.1 mmol) of copper (I)iodide and 58 mg (0.05 mmol) of tetrakis(triphenylphosphine)palladium.To this mixture was then added 0.14 mL (1.0 mmol) of triethylamine and0.27 mL (1.5 mmol) of triethylsilylacetylene as a solution in 1.5 mL ofdry DMF. The resulting mixture stirred at room temperature for 3 hours,at which time, 5.0 mL of water were added and the mixture extracted withethylacetate. The ethyl acetate extract was dried over MgSO₄ andconcentrated in vacuo. The resulting crude product was then purified bysilica-gel chromatography (7:1 hexanes/ethyl acetate) affording 194 mg(89%) of the title compound. LRMS: 481 (M+1), 341.

Method T 5-Ethynyl-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine

[0210] To a stirred solution of the product from Method S (194 mg/0.40mmol) dissolved in 2.0 mL of dry THF was added dropwise 0.4 mL (0.4mmol) of a 1 M solution of tetrabutylammonium fluoride in THF. Theresulting mixture stirred at room temperature for 10 minutes, then wastransferred to a methanol solution (3.0 mL) containing 1 gram of KOH,the new mixture stirred at room temperature for 15 minutes andconcentrated in vacuo. The residue was partitioned between water andethyl acetate, the ethyl acetate layer washed with water and brine,dried over MgSO₄ and concentrated to dryness in vacuo. The crude productwas purified by silica-gel chromatography (2:1 ethyl acetate/hexanes)affording 72 mg (64%) of the title compound as a white crystallinesolid. Mp 179-181° C. ¹H NMR (400 MHz) (CDCl₃) d: 1.72 (br s, 6H), 3.20(s, 1 H), 3.82-3.83 (m, 4H), 7.47 (s, 1 H), 8.35 (s, 1H). LRMS: 227(M+1).

1. A compound of the formula

or the pharmaceutically acceptable salt thereof; wherein R¹ is a group of the formula

wherein the dashed line represents optional double bonds; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; X, B and D are each independently oxygen, S(O)_(d) wherein d is 0, 1 or 2, NR⁶ or CR⁷R⁸; A and E are each CR⁷R⁸; and R⁶ is selected from the group consisting of hydrogen, (C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)alkyl (difluoromethylene), (C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl, (C₁-C₆)alkoxy(C₁-C₆)acyl, (C₁-C₆)alkylamino(C₁-C₆)acyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, (C₆-C₁₀)aryl, (C₅-C₉)heteroaryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl, (C₅-C₉)heteroaryl(C₁-C₆)alkyl, (C₆-C₁₀)aryl(C₆-C₁₀)aryl, (C₆-C₁₀)aryl(C₆-C₁₀)aryl(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, hydroxy(C₂-C₆)alkyl, (C₁-C₆)acyloxy(C₂-C₆)alkyl, (C₁-C₆)alkoxy(C₂-C₆)alkyl, piperazinyl(C₁-C₆)alkyl, (C₁-C₆)acylamino(C₁-C₆)alkyl, (C₆-C₁₀)aryl(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₅-C₉)heteroaryl(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkylthio(C₁-C₆)alkyl, (C₆-C₁₀)arylthio(C₁-C₆)alkyl, (C₁-C₆)alkylsulfinyl(C₁-C₆)alkyl, (C₆-C₁₀)arylsulfinyl(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl(C₁-C₆)alkyl, (C₆-C₁₀)arylsulfonyl(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl, R¹³CO(C₁-C₆)alkyl wherein R¹³ is R²⁰O or R²⁰R²¹N wherein R²⁰ and R²¹ are each independently selected from the group consisting of hydrogen, (C₁-C₆)alkyl, (C₆-C₁₀)aryl(C₁-C₆)alkyl or (C₅-C₉)heteroaryl(C₁-C₆)alkyl; or R¹⁴(C₂-C₆)alkyl wherein R¹⁴ is (C₁-C₆)acylpiperazino, (C₆-C₁₀)arylpiperazino, (C₅-C₉)heteroarylpiperazino, (C₁-C₆)alkylpiperazino, (C₆-C₁₀)aryl(C₁-C₆)alkylpiperazino, (C₅-C₉)heteroaryl(C₁-C₆)alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C₁-C₆)alkylpiperidyl, (C₆-C₁₀)arylpiperidyl, (C₅-C₉)heteroarylpiperidyl, (C₆-C₁₀)aryl(C₁-C₆)alkylpiperidyl, (C₅-C₉)heteroaryl(C₁-C₆)alkylpiperidyl, (C₁-C₆)alkoxyacyl, (C₁-C₆)alkylaminoaryl, ((C₁-C₆)alkyl₂aminoacyl or (C₁-C₆)acylpiperidyl; R⁷ and R⁸ are each independently selected from the group consisting of hydrogen, deuterium, (C₁-C₆)alkyl, amino, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)amino, (C₁-C₆)acylamino, (C₁-C₆)acyl(C₁-C₆)alkylamino, carboxy, (C₁-C₆)alkoxyacyl, (C₁-C₆)alkylaminoacyl, ((C₁-C₆)alkyl)₂aminoacyl, aminoacyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)alkyl (difluoromethylene), (C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl, (C₆-C₁₀)aryl, (C₅-C₉)heteroaryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl, (C₅-C₉)heteroaryl(C₁-C₆)alkyl, (C₆-C₁₀)aryl(C₆-C₁₀)aryl, (C₆-C₁₀)aryl(C₆-C₁₀)aryl(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₁-C₆)acyloxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, piperazinyl(C₁-C₆)alkyl, (C₁-C₆)acylamino(C₁-C₆)alkyl, piperidyl, (C₁-C₆)alkylpiperidyl, (C₆-C₁₀)aryl(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₅-C₉)heteroaryl(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkylthio(C₁-C₆)alkyl, (C₆-C₁₀)arylthio(C₁-C₆)alkyl, (C₁-C₆)alkylsulfinyl(C₁-C₆)alkyl, (C₆-C₁₀)arylsulfinyl(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl(C₁-C₆)alkyl, (C₆-C₁₀)arylsulfonyl(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl, R¹³CO(C₁-C₆)alkyl or R¹³CO(C₃-C₁₀)cycloalkyl wherein R¹³ is R²⁰O or R²⁰R²¹N wherein R²⁰ and R²¹ are each independently selected from the group consisting of hydrogen, (C₁-C₆)alkyl, (C₆-C₁₀)aryl(C₁-C₆)alkyl or (C₅-C₉)heteroaryl(C₁-C₆)alkyl; R¹⁴, R¹⁴(C₁-C₆)alkyl or R¹⁴(C₃-C₁₀)cycloalkyl wherein R¹⁴ is (C₁-C₆)acylpiperazino, (C₆-C₁₀)arylpiperazino, (C₅-C₉)heteroarylpiperazino, (C₁-C₆)alkylpiperazino, (C₆-C₁₀)aryl(C₁-C₆)alkylpiperazino, (C₅-C₉)heteroaryl(C₁-C₆)alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C₁-C₆)alkylpiperidyl, (C₈-C₁₀)arylpiperidyl, (C₅-C₉)heteroarylpiperidyl, (C₆-C₁₀)aryl(C₁-C₆)alkylpiperidyl, (C₅-C₉)heteroaryl(C₁-C₆)alkylpiperidyl or (C₁-C₆)acylpiperidyl; or a group of the formula

wherein p is 0, 1, 2 or 3; and Z is hydroxy, (C₁-C₆)alkoxy or NR¹R² wherein R¹ and R² are each independently selected from the group consisting of hydrogen, (C₁-C₆)alkyl, piperidyl, (C₁-C₆)alkylpiperidyl, (C₆-C₁₀)arylpiperidyl, (C₅-C₉)heteroarylpiperidyl, (C₆-C₁₀)aryl(C₁-C₆)alkylpiperidyl, (C₅-C₉)heteroaryl(C₁-C₆)alkylpiperidyl, (C₁-C₆)acylpiperidyl, (C₆-C₁₀)aryl, (C₅-C₉)heteroaryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl, (C₅-C₉)heteroaryl(C₁-C₆)alkyl, (C₆-C₁₀)aryl(C₆-C₁₀)aryl, (C₆-C₁₀)aryl(C₆-C₁₀)aryl(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, R⁵(C₁-C₆)alkyl, (C₁-C₅)alkyl(CHR⁵)(C₁-C₆)alkyl wherein R⁵ is hydroxy, (C₁-C₆)acyloxy, (C₁-C₆)alkoxy, piperazino, (C₁-C₆)acylamino, (C₁-C₆)alkylthio, (C₆-C₁₀)arylthio, (C₁-C₆)alkylsulfinyl, (C₆-C₁₀)arylsulfinyl, (C₁-C₆)alkylsulfoxyl, (C₆-C₁₀)arylsulfoxyl, amino, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂ amino, (C₁-C₆)acylpiperazino, (C₁-C₆)alkylpiperazino, (C₆-C₁₀)aryl(C₁-C₆)alkylpiperazino, (C₅-C₉)heteroaryl(C₁-C₆)alkylpiperazino, morpholino, thiomorpholino, piperidino or pyrrolidino; R⁶(C₁-C₆)alkyl, (C₁-C₅)alkyl(CHR⁶)(C₁-C₆)alkyl wherein R⁶ is piperidyl, (C₁-C₆)alkylpiperidyl, (C₆-C₁₀)arylpiperidyl, (C₆-C₁₀)aryl(C₁-C₆)alkylpiperidyl, (C₅-C₉)heteroarylpiperidyl or (C₅-C₉)heteroaryl(C₁-C₆)alkylpiperidyl; or when n is at least 1, D and E, or D and X, are each CR⁷R⁸, the adjacent R⁷ groups may be taken together, with the carbons to which they are attached, to form groups of the formulas

wherein the dashed lines represent optional double bonds; a is 0, 1 or 2; m, A, B and X are as defined above; and G, J, L and M are each independently oxygen, S(O)_(d) wherein d is 0, 1 or 2, NR⁶ or CR⁷R⁸ wherein R⁶, R⁷ and R⁸ are as defined above; or when n is 1, D and E are each CR⁷R⁸ and m is 1, A and B are each CR⁷R⁸, the respective adjacent R⁷ groups may be taken together, with the carbons to which they are attached, to form a group of the formula

wherein the dashed bond represent optional double bonds; a, G, J. L and M are as define above; r is 0 or 1; c is 0, 1 or 2; and R, W, Y and S are each independently oxygen, S(O)_(d) wherein d is 0, 1 or 2, NR⁶ or CR⁷R⁸ wherein R⁶, R⁷ and R⁸ are as defined above; R² and R³ are each independently selected from the group consisting of hydrogen, deuterium, amino, halo, hydoxy, nitro, carboxy, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, trifluoromethyl, trifluoromethoxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy wherein the alkyl or alkoxy groups are optionally substittued by one to three groups selected from halo, hydroxy, carboxy, amino (C₁-C₆)alkylthio, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₅-C₉)heteroaryl, (C₂-C₉)heterocycloalkyl, (C₃-C₉)cycloalkyl or (C₆-C₁₀)aryl; or R² and R³ are each independently (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkoxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₆-C₁₀)arylamino, (C₁-C₆)alkylthio, (C₆-C₁₀)arylthio, (C₁-C₆)alkylsulfinyl, (C₆-C₁₀)arylsulfinyl, (C₁-C₆)alkylsulfonyl, (C₆-C₁₀)arylsulfonyl, (C₁-C₆)acyl, (C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyamino-CO—, (C₅-C₉)heteroaryl, (C₂-C₉)heterocycloalkyl or (C₆-C₁₀)aryl wherein the heteroaryl, heterocycloalkyl and aryl groups are optionally substituted by one to three halo, (C₁-C₆)alkyl, (C₁-C₆)alkyl-CO—NH—, (C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyl-CO—NH—(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH—(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH—(C₁-C₆)alkoxy, carboxy, carboxy(C₁-C₆)alkyl, carboxy(C₁-C₆)alkoxy, benzyloxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₆-C₁₀)aryl, amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonylamino, (C₆-C₁₀)aryl(C₁-C₆)alkoxycarbonylamino, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₁-C₆)alkylamino(C₁-C₆)alkyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, carboxy, carboxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyl-CO—NH—, cyano, (C₅-C₉)heterocycloalkyl, amino-CO—NH—, (C₁-C₆)alkylamino-CO—NH—, ((C₁-C₆)alkyl)₂amino-CO—NH—, (C₆-C₁₀)arylamino-CO—NH—, (C₅-C₉)heteroarylamino-CO—NH—, (C₁-C₆)alkylamino-CO—NH—(C₁-C₆)alkyl, ((C₁-C₆)alkyl)₂amino-CO—NH—(C₁-C₆)alkyl, (C₆-C₁₀)arylamino-CO—NH—(C₁-C₆)alkyl, (C₅-C₉)heteroarylamino-CO—NH—(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₁-C₆)alkyisulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₆-C₁₀)arylsulfonyl, (C₆-C₁₀)arylsulfonylamino, (C₆-C₁₀)arylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₅-C₉)heteroaryl or (C₂-C₉)heterocycloalkyl; with the proviso that when A, B or X, in formulas V or VI, is defined as NR⁶ or CR⁷R⁸, R² and/or R³ must be halo; with the proviso that when R² and R³ are each independently hydrogen or (C₁-C₆)alkyl, R¹ cannot be unsubstituted piperidinyl; with the proviso that when R² and R³ are each hydrogen, R¹ cannot be unsubstituted mopholinyl or pyrrolidinyl; with the proviso that when R² and R³ are each hydrogen, R¹ cannot be piperazinyl; and with the proviso that the groups of formulas IV, V, VI or XIII do not contain two or more oxygens, sulfurs or combinations thereof in adjacent positions.
 2. A compound according to claim 1, wherein R¹ is a group of the formula

wherein the dashed line represents optional double bonds; m is 0, 1, 2or 3; n is 0, 1, 2 or 3; X, B and D are each independently oxygen, S(O)_(d) wherein d is 0, 1 or 2, NR⁶ or CR⁷R⁸; A and E are each independently CR⁷R⁸or NR⁶; or when n is 1, D and E are each CR⁷R⁸ and m is 1, A and B are each CR⁷R⁸, the respective adjacent R⁷ groups may be taken together, with the carbons to which they are attached, to form a group of the formula

wherein the dashed bond represent optional double bonds; a, G, J. L and M are as define above; r is 0 or 1; c is 0, 1 or 2; and R, W, Y and S are each independently oxygen, S(O)_(d) wherein d is 0, 1 or 2, NR⁶ or CR⁷R⁸ wherein R⁶, R⁷ and R⁸ are as defined above.
 3. A compound according to claim 1, wherein R² and R³ are each independently selected from the group consisting of hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkoxy, (C₂-C₉)heterocycloalkyl, (C₅-C₉)heteroaryl or (C₆-C₁₀)aryl.
 4. A compound according to claim 1, wherein said compound is selected from the group consisting of: 5-Fluoro-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine; 4-Piperidin-1-yl-5-trifluoromethyl-7H-pyrrolo[2,3-d]pyrimidine; 2-{3-Ethyl-4-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-cyclopentyl}propan-2-ol; 2-{3-Ethyl-4-[(2-hydroxy-ethyl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-cyclopentyl}-propan-2-ol; N,N-Dimethyl-N′-[3-(4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-benzyl]-ethane-1,2-diamine; 2-[1-(5-m-Tolyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-ethanol; 5-(3-Isopropyl-phenyl)-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine; 5-(3-Methyl-3H-imidazol-4-yl)-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine; 5-(1-Methyl-1H-imidazol-4-yl)-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine; 5-(2-Methyl-pyridin-4-yl)-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine; 5-Chloro-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine; 5-Chloro-4-(octahydro-indol-1-yl)-7H-pyrrolo[2,3-d]pyrimidine; 5-Ethynyl-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine; 4-Piperidin-1-yl-5-m-tolyl-7H-pyrrolo[2 ,3-d]pyrimidine; and 4-(3,3-Dimethyl-piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine.
 5. A pharmaceutical composition for (a) treating or preventing a disorder or condition selected from organ transplant rejection lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases or (b) the inhibition of protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human, comprising an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, effective in such disorders or conditions and a pharmaceutically acceptable carrier.
 6. A pharmaceutical composition for (a) treating or preventing a disorder or condition selected from organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases or (b) the inhibition of protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human, comprising an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional agents which modulate a mammalian immune system or with antiinflammatory agents, effective in such disorders or conditions and a pharmaceutically acceptable carrier.
 7. A method for the inhibition of protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
 8. A method for treating or preventing a disorder or condition selected from organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases in a mammal, including a human, comprising administering to said mammal an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, effective in treating such a condition.
 9. A method for the inhibition of protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof alone or in combination with one or more additional agents which modulate a mammalian immune system or with antiinflammatory agents.
 10. A method for treating or preventing a disorder or condition selected from organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases in a mammal, including a human, comprising administering to said mammal an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional agents which modulate a mammalian immune system or with antiinflammatory agents, effective in treating such a condition. 